ASCO 2026 GU Cancer Highlights: Beyond the LBAs

The 2026 ASCO Annual Meeting featured several late-breaking abstracts in genitourinary (GU) oncology, but the full GU program at the conference offered a wealth of additional clinically meaningful data. The following highlights capture key findings from across the meeting in bladder cancer, prostate cancer, and renal cell carcinoma.

Next-Generation Nectin-4 ADC Shows Activity After Enfortumab Vedotin Failure in Urothelial Carcinoma

LY4052031, an investigational Nectin-4 antibody-drug conjugate (ADC) built around a topoisomerase I inhibitor payload, produced confirmed responses in one-third of patients with metastatic urothelial carcinoma (mUC) who had progressed on prior enfortumab vedotin (Padcev; EV)-based therapy, according to first-in-human results from the phase 1 NEXUS-01 study (NCT06465069).¹

Among 36 evaluable mUC participants with prior EV exposure and intact CYP2D6 function, the overall response rate (ORR) was 33%, the disease control rate (DCR) was 75%, and the median duration of response (DOR) was 7.4 months, with 67% of responses ongoing at data cutoff. At the 3.6 mg/kg dose level, ORR climbed to 47% in 15 post-EV-exposed patients. Among EV-naive participants, ORR was 67%. No confirmed responses were observed in 18 patients who had received a prior topoisomerase I-payload ADC.

CYP2D6 metabolizer status significantly influenced payload exposure and toxicity risk. Poor metabolizers had approximately 5-fold higher payload exposure than normal metabolizers, with substantially higher rates of grade ≥3 mucositis, neutropenia, febrile neutropenia, and sepsis. The protocol was amended to require prospective CYP2D6 genotyping and enrollment of poor metabolizers has been halted. In the normal metabolizer population (n = 122), LY4052031 was generally well tolerated, with nausea (40%), dysgeusia (38%), alopecia (37%), and fatigue (30%) as the most common any-grade events. EV-associated toxicities such as peripheral neuropathy and skin toxicity were rare.

Durvalumab Plus BCG Maintains Favorable OS and Quality of Life at 5 Years in NMIBC

Updated 5-year overall survival (OS) and patient-reported outcome (PRO) data from the phase 3 POTOMAC trial (NCT03528694) show that the addition of durvalumab (Imfinzi) to Bacillus Calmette-Guérin (BCG) induction and maintenance therapy does not negatively impact OS or quality of life (QOL) in patients with BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC), further supporting the regimen's FDA approval.²

At a median follow-up of 72 months, the 5-year OS rate was 88% with durvalumab plus BCG induction and maintenance (n = 339) vs 86% with BCG induction and maintenance alone (n = 340; HR, 0.81; 95% CI, 0.54-1.19), with median OS not reached in either arm. The FDA approval of durvalumab plus BCG for BCG-naive high-risk NMIBC was based on the prior POTOMAC disease-free survival (DFS) analysis, which demonstrated a 32% reduction in the risk of high-risk disease recurrence or death (HR, 0.68; 95% CI, 0.50-0.93; P =.0154).

Patient-reported outcomes assessed via the EORTC QLQ-C30 and EORTC QLQ-NMIBC24 showed similar trajectories between arms, with no differences reaching clinically meaningful thresholds. Rates of PRO-CTCAE symptom worsening were largely comparable, though urinary frequency and interference were numerically higher in the durvalumab arm.

"The addition of durvalumab to BCG induction and maintenance continued to show no detriment at the planned 5-year OS analysis, and it did not have a major impact on patient-reported QOL," said lead author Maria De Santis, MD, head of the Interdisciplinary Uro-Oncology Section at Charité-University Medicine Berlin.

Treatment Interruption Feasible in Exceptional Responders With Metastatic HSPC

For patients with metastatic hormone-sensitive prostate cancer (HSPC) who achieve exceptional responses to androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI), treatment interruption may be feasible without immediate disease progression, according to the phase 2 A-DREAM/Alliance A032101 trial (NCT05241860).³

Among 78 responders who underwent treatment suspension, 45 (57.7%) remained treatment free at 18 months, 32 (41.0%) of whom also experienced testosterone recovery. A total of 52 patients (66.7%) experienced testosterone recovery regardless of treatment-free status. The primary end point, 18-month treatment-free survival with testosterone recovery, was met, with 38.5% of patients remaining off treatment at a median follow-up of 26.9 months (80% CI, 33.1%-48.9%; P =.0249). The median duration off treatment was 24.5 months (95% CI, 19.3-not evaluable [NE]).

Subgroup analyses showed that high-volume disease was associated with a higher likelihood of requiring subsequent therapy (HR, 3.05; 95% CI, 1.60-5.81), while receipt of radiation to metastatic sites was associated with a lower likelihood (HR, 0.42; 95% CI, 0.18-0.94). The 24-month radiographic progression-free survival (rPFS) rate was 80.7% (95% CI, 71.5%-91.1%) and the 24-month OS rate was 95.0% (95% CI, 91.7%-100.0%), though both end points remained immature.

"The study met its primary end point with 41% of patients remaining treatment free with testosterone recovery 18 months after stopping ADT and ARPI," said lead author Atish D. Choudhury, MD, PhD, of Dana-Farber Cancer Institute.³ "Only 1 of the 4 deaths observed on the study have been from prostate cancer."

Lutetium PSMA Triplet Benefit Consistent Across Disease Volume and mHSPC Subgroups

Subgroup analyses from the phase 3 PSMAddition trial (NCT04720157) demonstrate that adding lutetium Lu 177 vipivotide tetraxetan (Pluvicto) to ADT plus an ARPI produces consistent rPFS benefit regardless of disease volume or de novo vs recurrent disease status in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC).⁴

Across all 4 prespecified and exploratory subgroups, HRs for rPFS with the triplet vs ADT/ARPI alone ranged from 0.72 to 0.74, closely tracking the overall population HR of 0.72 (95% CI, 0.58-0.90; P =.002). Specifically, the rPFS HR was 0.72 (95% CI, 0.56-0.92) in high disease volume patients and 0.73 (95% CI, 0.42-1.27) in low disease volume patients; in de novo patients the HR was 0.74 (95% CI, 0.54-1.01) and in recurrent patients it was 0.74 (95% CI, 0.53-1.04). Benefits in time to PSA progression and time to metastatic castration-resistant prostate cancer followed consistent directional patterns across all subgroups.

The safety profile was similarly consistent. Grade ≥3 adverse events occurred in 47% to 53% of triplet-arm patients across subgroups versus 39% to 46% in controls. Cytopenias (41%-47% triplet vs 18%-22% control) and dry mouth (43%-51% vs 3%-5%) were the most notable toxicities of special interest across all subgroups.

ctDNA-Guided Adjuvant Atezolizumab Preserves Quality of Life in MIBC

Patient-reported outcome (PRO) data from the phase 3 IMvigor011 trial (NCT04660344_ show that ctDNA-guided adjuvant atezolizumab (Tecentriq) has minimal impact on functioning and QOL vs placebo in patients with muscle-invasive bladder cancer (MIBC) who test ctDNA positive after cystectomy.⁵

Across all EORTC QLQ-C30 domains, no clinically meaningful differences between arms were observed. Time to confirmed deterioration in physical functioning was 25.1 months (95% CI, 18.5-NE) with atezolizumab vs NE (95% CI, 19.4-NE) with placebo (HR, 1.25; 95% CI, 0.76-2.07); for role functioning, 18.5 months vs NE (HR, 1.45; 95% CI, 0.88-2.40); and for global health status/QOL, 35.4 months vs 16.5 months (HR, 0.71; 95% CI, 0.45-1.12). From cycle 1, day 1 through cycle 11, day 1, more than 90% of patients in both arms reported little to no adverse effect burden per EORTC IL46. Patient-reported symptom rates including constipation, diarrhea, nausea, pain, and fatigue were similar between arms throughout treatment.

"There were no clinically meaningful differences in symptoms, functioning, or global health status/QOL over time," wrote lead author Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center at Dana-Farber Cancer Institute. "The vast majority of patients reported little or no adverse effect burden."

These PRO findings complement the previously reported DFS and OS benefit of ctDNA-guided atezolizumab in IMvigor011 and support the tolerability of this approach in a post-cystectomy population.

REFERENCES

1. Iyer G, Gao X, Wei AZ, et al. Initial results from NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma. J Clin Oncol. 2026;44(suppl 16):4508. doi:10.1200/JCO.2026.44.16_suppl.4508

2. De Santis M, Shore ND, Nishiyama H, et al. Durvalumab (D) in combination with BCG induction and maintenance (I+M) therapy for BCG-naïve, high-risk non-muscle-invasive bladder cancer (NMIBC): 5-year overall survival (OS) analysis and patient-reported outcomes (PROs) from POTOMAC. J Clin Oncol. 2026;44(suppl 16):4624. doi:10.1200/JCO.2026.44.16_suppl.4624

3. Choudhury AD, Ballman KV, Reimers MA, et al. A phase 2 trial of androgen deprivation therapy interruption in patients responding exceptionally to androgen receptor pathway inhibitor in metastatic hormone-sensitive prostate cancer (A-DREAM/Alliance A032101). J Clin Oncol. 2026;44(suppl 16):5004. doi:10.1200/JCO.2026.44.16_suppl.5004

4. Saad F, Tagawa ST, Sartor O, et al. Subgroup analyses by disease volume and de novo/recurrent mHSPC in the PSMAddition study of [177Lu]Lu-PSMA-617. J Clin Oncol. 2026;44(suppl 16):5020. doi:10.1200/JCO.2026.44.16_suppl.5020

5. Bellmunt J, Gupta S, Durán MÁ, et al. Patient-reported outcomes from IMvigor011: a phase 3 study of circulating tumor (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer (MIBC). J Clin Oncol. 2026;44(suppl 16):4627. doi:10.1200/JCO.2026.44.16_suppl.4627